Registration Dossier

Administrative data

Description of key information

subacute oral NOAEL = 20 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Remarks:
BASF AG
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Age at study initiation: 11-12 weeks (males), 10-11 weeks (females)
- Housing: individually, DKII stainless stell cages/ Makrolon type M II cages
- Diet (ad libitum): Kliba maintenance diet mouse/rat
- Water (ad libitum):drinking water
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: gavage
Vehicle:
other: doubly distilled water
Details on oral exposure:
The daily volume administered was 10 ml/kg-bw based on most recent individual body weight
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 29 days (approx. 2 weeks premating, 2 weeks mating and post mating)
Females: 50 days (premating, mating and gestation through day 4 after delivery)
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
20, 60, 200 mg/kg bw
Basis:
other: Administered dose by gavage
No. of animals per sex per dose:
10
Control animals:
yes
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before first dose and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Regularly during premating, after the mating period and, in dams, during gestation and lactation periods.

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Males on study day 29, Females on study day 50
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- Animals fasted: No data
- How many animals: 5

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Males on study day 29, Females on study day 50
- Animals fasted: No data
- How many animals: 5

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Males on study day 28, Females on study day 42
- Dose groups that were examined: low, medium, and high dose groups
- Battery of functions tested: functional battery and motor activity measurement
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
High dose group only. Salivation (males / females) and impairment of motor activity (males)
Mortality:
mortality observed, treatment-related
Description (incidence):
High dose group only. Salivation (males / females) and impairment of motor activity (males)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose group only (males / females).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
High dose group only (males / females).
Food efficiency:
not examined
Description (incidence and severity):
Oral gavage study
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
Oral gavage study
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Mid and high dose females only. Decreased hemoglobin and hematocrit
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
High dose only. Increased potassium, inorganic phosphate and albumin (males / females) and increased total bilirubin in males and calcium and magnesium (females only).
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Mid and high doses (males / females). Liver and kidneys
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mid and high dose (males and/or females). Minimal to moderate storage of alpha 2u protein in epithelial cells of proximal tubules, minimal to moderate centrolobular hypertrophy in the liver, minimal to slight hypertrophy/hyperplasia of the thyroid follic
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity F0 animals
Critical effects observed:
not specified

The following test substance-related findings were obtained:

Test group 3 (200 mg/kg-bw/day)

F0 parental animals

CLINICAL EXAMINATIONS

  • salivation in males after treatment from second week onwards
  • slight impairment of motor activity in males from interval 1 to 6
  • significant reduction in food consumption during the first week of treatment in both sexes (-12% males and -17% females)
  • significant impairment of body weights and body weight gain (max.-9% and -59%, respectively) in males
  • significant impairment of females body weights and body weight gain in study weeks 6 and 7 (max.-16% and -8%, respectively)

CLINICAL PATHOLOGY

  • increased potassium, inorganic phosphate and albumin in both sexes
  • increased total bilirubin in males and calcium and magnesium in females
  • decreased creatinine and glucose in males and hemoglobin, hematocrit and chloride in females

PATHOLOGY

  • significant decrease in terminal body weight in males and females
  • significant increase of relative kidney weights in male animals
  • significant increase of absolute and relative liver weights in male and female animals
  • minimal to moderate storage of alpha 2u protein in epithelial cells of proximal tubules in all male animals
  • minimal to moderate centrolobular hypertrophy in the liver of nine male and nine female animals
  • minimal to slight hypertrophy/hyperplasia of the thyroid follicular cells of three female animals

Test group 2 (60 mg/kg-bw/day)

F0 parental animals

CLINICAL EXAMINATIONS

  • no test substance-related effects in F0 males and F0 females were observed

CLINICAL PATHOLOGY

  • decreased hemoglobin and hematocrit in females

PATHOLOGY

  • significant increase of absolute and relative kidney weights in male animals
  • significant increase of absolute and relative liver weight in males
  • significant increase of relative liver weights in females
  • minimal to slight storage of alpha 2u protein in epithelial cells of proximal tubules in five male animals
  • minimal centrolobularhypertrophy in the liver of four female animals

Testgroup 1 (20 mq/kg-bw/dav)

F0 parental animals

CLINICAL EXAMINATIONS / CLINICAL PATHOLOGY / PATHOLOGY / FEMALES

CLINICAL EXAMINATIONS DURING GESTATION AND LACTATION/ FERTILITY /REPRODUCTIVE PERFORMANCE

  • no treatment-related effects were observed
Conclusions:
In conclusion, the gavage administration of 200 mg/kg body weight/day 2-Butene-1,4-diol to male and female Wistar rats caused distinct systemic toxicity such as salivation, markedly reduced food consumption and retarded body weight development, liver enzyme induction, storage of alpha 2µ protein and mild impairment of motor activity in the males as well as mild anemia in the females.

The NOAEL of the test substance for general, systemic toxicityis 20 mg/kg of bodyweight/day for the F0 parental rats of both sexes.
Executive summary:

Based on 50 -day female results, Buttendiol will be classified as R48, therefore no 90 -day sub-chronic study is warranted.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In an OECD Guideline 422 study, the oral gavage administration of 200 mg/kg body weight/day 2-Butene-1,4-diol to male and female Wistar rats caused distinct systemic toxicity such as salivation, markedly reduced food consumption and retarded body weight development, and mild impairment of motor activity in the males. A dose of 60 mg/kg of body weight/day still evoked liver enzyme induction in both genders, storage of alpha 2µ protein in males and mild anemia in females. The NOAEL of the test substance for general, systemic toxicity is 20 mg/kg of bodyweight/day for the F0 parental rats of both sexes (BASF AG, 2006). Repeat dose toxicity was not determined via inhalation or dermal exposure.

Justification for classification or non-classification

1,4-Butenediol (B2D) is classified as Xn; R48/22 (Harmful, danger of serious damage to health by prolonged exposure if swallowed) under the EU DSD 67/548/EEC, and as Specific Target Organ Toxicity - Repeated Exposure (STOT-RE), Category 2 under Annex VI of Regulation (EC) 1272/2008, based on the results (effects were observed at 60 mg/kg) of an OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test).